The liver functions in the clearance of a large variety of metabolic products, drugs and other xenobiotics by transporting them across the sinusoidal membrane into the hepatocyte. Several classes of transport systems have been described that mediate these processes including the Na+/taurocholate cotransporter polypeptide, NTCP, in rat and human liver (Hagenbuch, B., et al. (1991) Proc. Natl. Acad. Sci. USA 88:10629-33; Hagenbuch, B. et al., (1994) J. Clin. Invest. 93:1326-31) and a family of organic anion transporting polypeptides (OATPs) that are principally expressed in liver, kidney and brain, and transport a broad spectrum of substrates in a sodium-independent manner (Meier, P. J., et al., (1997) Hepatology 26:1667-77; Wolkoff, A. W., (1996) Semin. Liver Dis. 16:121-127). The distribution of this latter family of transporters in liver, kidney and choroid plexus in the brain is thought to reflect common physiological requirements of these organs for the clearance of a multitide of organic anions. There are three OATP isoforms in the rat: roatp1 (Jacquemin, E., et al., (1994) Proc. Natl. Acad Sci. USA 91:133-37); roatp2 (Noe, B. A., et al., (1997) Proc. Natl. Acad. Sci. USA 94:10346-50; and roatp3 (Abe, T., et al., (1998) J. Biol. Chem. 273:11395-401). In addition to bile acids, OATPs are known to transport a variety of other compounds. These include, depending on the transporter, unconjugated and conjugated steroids such as estrone sulfate, estradiol-17B-glucuronide, aldosterone, and cardiac glycosides (Boussuyt, X., et al., (1996) J. Pharmacol. Exp. Ther. 276:891-6; Boussuyt, X. (1996) J. Hepatol. 25:733-8; Kanai, N., et al., (1996) Am. J. Physiol. 270:F319-F325; Kanai, N., et al., (1996) Am. J. Physiol. 270:F326-F331; Noe, B. A., et al., (1997) Proc. Natl. Acad. Sci. USA 94:10346-50). Bromosulfophthalien (Jacquemin, E., et al., (1994) Proc. Natl. Acad. Sci. USA 91:133-7); mycotoxin (Kontaxi, M., et al., (1996) J. Pharmacol. Exp. Ther. 279:1507-13); leukotriene C4 (Li, L., et al., (1998) J. Biol. Chem. 273:16184-91); and thyroid hormone (Abe, T., et al., (1998) J. Biol. Chem. 273:11395) are additional substrates.
Several proteins have been identified. Jacquemin,E., et al., (1994) Proc. Natl. Acad. Sci. U.S.A., 91:133-137 reported the first cloning and identification of a member of the OATP transporter family, namely the rat oatp1. The first cloning and identification of a human OATP was reported in Kullak-Ublick, G. A., et al., (1995) Gastroenterology, 109:1274-1282. Its expression was found in liver, kidney brain and other organs. The authors concluded, based on substrate specificities, that it was not the human orthologue of rat oatp1.
Substrate specificities of rat oatp1 are discussed in Kullak-Ublick, G. A. et al., (1994) Hepatology, 20:411-416, while substrate specificities of human OATP are discussed in Bossuyt, X., et al., (1996) J. Hepatol., 25:733-738.
Data was later discovered showing that rat oatp1 is involved in the transport of steroids (Bossuyt, X., et al., (1996) J. Pharmacol. Exp. Ther., 276:891-896), and that human OATP acts as a transporter for the psychoactive hormone DHEAS (Kullak-Ublick, G. A., et al., (1998) FEBS Lett., 424:173-176). For a review of the OATP family and organic anoin transport in the liver, see Wolkoff, A. W., (1996) Semin. Liver Dis., 16:121-127.
A third rat OATP isoform that was shown to transport thyroid hormones T3 and T4 was cloned and reported in Abe, T., et al., (1998) J. Biol. Chem., 273:22395-22401.
All references cited herein, whether supra or infra, are hereby incorporated by reference in their entirety.